Take a Breath! Managing Breathing Problems after Transplant

Presenter:  Kenneth Cooke MD, The Sidney Kimmel Cancer Center at Johns Hopkins

This is a video of a presentation at the 2018 Celebrating a Second Chance at Life Survivorship Symposium in Denver, Co.

Presentation is 37  minutes with 17 minutes Q & A

Summary: Up to 50% of people develop lung problems after a transplant using donor cells. Some are caused by infection. Graft-versus-host disease can cause bronchiolitis obliterans syndrome (BOS). Frequent pulmonary function tests are important to catch breathing problems early after transplant.

Highlights

• Lung injury is common in transplant recipients who receive donor stem cells
• 50 percent of lung problems are caused by infection
• Graft-versus-host disease can also cause lung injury after transplant

Key Points:

• 06:17  Anatomy and function of lungs
• 08:54  What does a pulmonary function test measure? 
• 15:17  Bacteria, fungi and viruses that can cause infection in the lungs
• 16:01  Idiopathic pneumonia syndrome (IPS) describes infections whose source cannot be traced
• 17:57  Etanercept (Enbrel) is used to treat idiopathic pneumonia syndrome or IPS
• 18:35  Bronchiolitis obliterans syndrome (BOS) affects 5-10% of patients after transplant
• 23:04  Pulmonary problems often don’t have symptoms early in the course of the disease
• 24:24  Bronchiolitis obliterans syndrome with organization pneumonia (BOOP) is a rare complication after transplant
• 31:35  Regular pulmonary function tests are important to detect and manage GVHD in the lungs
• 32:55  Medicines available to treat GVHD in the lungs include Enbrel, Ibrutinib, FAM and extracorporeal photopheresis

Transcript of Presentation

00:00  How to manage lung problems after bone marrow transplant:  I'm going to talk about managing lung problems after bone marrow transplant. It's meant to be interactive. If you want to ask questions later, if there's something burning, raise your hand and we'll talk about it as the presentation goes on. I'm not even sure how important this is. I will be talking about a drug very briefly called Enbrel or etanercept, which is not approved for lung injury. But anytime that happens, that has to be disclosed. I also like to tell people, I like to talk, Rodney would probably know that. And I'm also a Yankee fan, I always feel like I have to disclose that because if you want to get up and leave, it's okay to do so. So there's a couple of objectives. I'm going to start, I know you know this already, but I just want to highlight a couple of concepts about bone marrow transplant and graft-versus-host disease before we actually get into reviewing lung anatomy function and testing.

00:52  Overview of Presentation:  I think in order to figure out or to understand what's going on with a lung problem, I think it's helpful if you understand how the lung works, and basically how the lung is set up in the body. And then we'll talk specifically about certain lung problems, infectious versus non-infectious, early versus late. And in that context, think of the lung as a target organ of this graft-versus-host disease. And we're going to talk about some tests and procedures that may need to be completed to diagnose and treat lung problems.

01:07  So here's just an overview of bone marrow transplant. You guys in the room are going to be familiar with this, I guess it just helps me kind of warm up a little bit. As you heard today, I think in that spectacular video, this really started out as a more is better approach.

You heard about total body irradiation, high doses of chemotherapy. Some of you may have very well also have received high doses of treatment as well when this is kind of super lethal anticancer therapy. Now, this has actually kind of moved toward a more gentler approach with reduced intensity preparative regimens. And then as you guys know, there's this donor stem cell rescue. There are many limitations to the use of bone marrow transplant even though it still remains the only curative therapy for many patients with both malignant and non-malignant disorders of the blood and immune system. And we know that there are, what we call, regimen related toxicities. We heard the stories today, and you guys have probably been through this before as well. Our patients are prone to infection and bleeding and problems with many of the organs in the body.

Graft-versus-host disease is a big issue when you're getting blood stem cells from someone other than self. And we're going to speak the rest of the time about lung injury and dysfunction that can occur again either early or late or of the infectious or non-infectious flavor. So you should be very familiar with this.

Here's the procedure. Here is the patient, P for patient. Maybe this patient has some hidden leukemia cells, as I like to say until we have Star Trek technology where I can kind of put a wand up to someone's body and say, "You have no evidence of leukemia." Sometimes we think there may be some hidden cells, but our patients come into the transplant unit. They're going to get some combination of chemotherapy, maybe radiation. What does that do? It wipes out the blood in the immune systems. Then there's a choreographed effort to find that suitable donor, collect those donor, D for donor stem cells.

They get infused into your central venous catheter. And really, by God's grace, those cells get into the blood and into the bone marrow. And over the course of about three to four weeks, those donor stem cells are going to give rise to white cells, red cells, and platelets and really reestablish the blood in the immune systems.

03:49:  Graft-versus-host disease occurs when the donor’s cells attack the patient’s organs and tissues: one or two slides on this and then we'll move on to lung injury. When I talk to patients and families, I'm actually a pediatrician by training. So I really have to try to get down and explain this in a way that patients and families are going to understand. And I start out by saying graft-versus-host disease simply put could be considered the opposite to what occurs after a solid organ transplant. So if you're going to get a heart, a kidney or a lung or what have you, it's really the patient's immune system rejecting the donor organ. But graft-versus-host disease is this process turned all the way around.

Donor organ or the stem cell graft that rejects the host or patient, hence the term graft-versus-host disease. This is a major complication, we heard about it today in the video. It can be life-threatening, it's always a risk unless the donor and host are identical twins. And we do know that the damage is caused by the donor immune system, by special cells called lymphocytes, and they can target and cause problems with the skin, the liver, the intestinal tract and the lung, which is going to be the topic of our conversation.

05:03 Do you have GVHD in transplants using cells from an identical twin? I've probably done, I can count on one hand, probably a couple of fingers, the number of identical twin transplants that we've done. But yes, sometimes ... So the issues are sometimes you worried if the identical twin is going to somehow come down with the same disorder.

Is that possible?

Well, this is what you may be also alluding to. So these T-cells also have very powerful graft versus leukemia effects. And it may very well have been that your physicians and practitioners may have said, "Look, you're too good of a match. Your sister cells are not going to be able to help attack your leukemia." So that's important. And if we have time later, I can give you a little metaphor that helps explain graft-versus-host disease and graft versus leukemia effects. But it's a little bit of a digression. But if we have time later, I have a slide that will show that. And what the goal, I think of bone marrow transplant is to have a strategy that's going to reduce the damage of this graft-versus-host disease, facilitate the restoration of blood in immune systems and preserve these graft-versus-leukemia effects. This is the holy grail for us as blood stem cell transplant physicians.

06:17  Anatomy and function of lungs:  So let's move on to the lung. So when I talk to people about the lung, trying to put it down in a way that people can get their arms around, I ask them to think about a tree. Not just a tree, a tree upside down. And then you can begin to understand the anatomy of the lungs.

So, the trunk of the tree is your trachea, that's your wind pipe. And it turns out the big branches of the tree are called bronchi. The smaller bronchiole, the smaller branches are called bronchioles. And all the way down at the bottom we'll see where the leaves are, the air sacs are called alveoli. But keep this in mind, and not maybe just the picture of a tree, but the tree that are out there now in the springtime just before the leaves are about to bloom again.

You can go through the anatomy thinking of that trachea or the main trunk.  And then the primary branches, and then all the way down to the tweaks, the terminal bronchioles. And right at the end of the twigs, you have the leaf buds. And that's where the alveoli are, and that is where gas exchange occurs.

07:20  Which part of the lungs are affected by various diseases? So, if we think for a second, if your doctor says you have bronchitis, now you know what the heck they're talking about. It's these main branches of the trees that are inflamed or infected. It may be from a germ. People who smoke can have chronic bronchitis. It just means that this part of the airway, this part of the bronchial tree is inflamed.

Some people will have bronchiolitis obliterans, we're going to talk a lot about that. Where is that? That's all the way down the little twigs right before you get to the leaf buds. They are the bronchioles. When you have inflammation there, you add itis to the name, bronchiolitis.

If you have pneumonia, well, then it's these alveolar structures, and I'll show you some cartoons, that are filled with pus and infection. Does that make sense? Here are the alveolar structures right here, they look like little grapes. That's where gas exchange occurs.

08:11  What happens when you breathe normally?  So, what happens with normal breathing? This is a little bit more of a medical slide, but let's still go through. Here's the trachea, the main branches, the main bronchi, all the way down to these alveolar structures. They almost look like broccoli, right? This is where gas is exchanged, where oxygen is taken out of the lungs and bad gases like carbon dioxide are brought back from the blood and into the lungs. And then the carbon dioxide can be expelled. And this happens to a very, very, very thin membrane. And you can imagine if this membrane gets thickened, if it gets inflamed, you can have problems with getting gas in and out of the body.

08:54  What does a pulmonary function test measure?  So, pulmonary function tests, probably one of your favorites pastimes. Right. Getting into one of these pulmonary function test bubbles, having something on your nose, and hopefully having a good coach that is going to take you through the procedure. I want to take you through this so you understand when you finally get your pulmonary function test report what this is all about.

So, this is lung basics, pulmonary function testing. So let's start right here. There's a whole bunch of measurements that are going to be taken. But each one of us, as we're in the room, we're breathing air in and out, in and out. And then the technician will say, "Take a deep breath in and blow out as hard as you can." So this kind of represents normal breathing and then a deep breath. So how are these things being measured?

09:39  What is tidal volume, residual volume , forced vital capacity and total lung capacity?  It is just the amount of air that is going in and out of our lungs right now as we're sitting watching this. Now, hopefully none of you are getting excited and breathing faster. But if you're just breathing nice and slow, that's your tidal volume.

If someone says, "Take a big deep breath in," that will get you to your forced vital capacity or FVC.

Residual volume is after you take a big breath in and blow it all out, your lungs are never fully collapsed. There's always air left to keep your lungs expanded, that is called residual volume. And your total lung capacity is basically your forced vital capacity plus your residual volume. So that is all the air that can be in your lungs. TLC, Total Lung Capacity, FVC, Forced Vital Capacity. And we're going to talk about one other measurement in a moment.

So here we are again, you're in the pulmonary function bubble. You're taking regular breaths in and out and in and out. The technician says, "Take a big, big breath in, and then blow out as hard as you can." So again, we're going to go all the way up to forced vital capacity, and then you're going to blow that all the way down. And they're going to measure how much air you get out of your lungs in the first second. And that is called forced expository volume one.

Residual volume, again, is at the very bottom. After you blow all of your air out, there is a little bit of residual volume, something that's going to keep your lungs filled. So anytime you see pulmonary function tests, I tell my patients it reads like a report card. The closer you are to 100%, the better because based upon how old you are, if you're male or female and what our background is and your height, they will give you predicted measurements.

You're predicted to have a FVC of four liters. And if you blow out 3.5 liters, you will get a percent. And again, the closer you are to 100%, the better. And that's where my report card metaphor comes from.

11:48  Lung injury occurs in up to 50% of patients after transplant:  So, let's think about some problems with the lungs after transplant. So it turns out that lung injury is actually still a major complication of transplant and can actually occur in up to 50% of our patients. It can occur early and late. And I will tell you this week alone, I was at the National Institutes of Health on Wednesday and Thursday for a conference specifically dedicated to lung injury after transplant, particularly in pediatric patients. And then I was at Memorial Sloan Kettering on Friday, a whole symposium looking at toxicity of transplants. I want to tell you, I want to try to reassure you, there is a lot of energy and effort going into making transplants safer and figuring out how we can prevent and treat lung injury after transplant, and that is ongoing as we speak.

12:39  Timeline of when lung problems can occur after transplant:  Now, I mentioned before, about half of the cases can be infectious so you can have some kind of germ, bacteria, a fungus or a virus. We're going to talk a little bit about this. But the other half of lung injuries are non-infectious. So, this is where we get into this possibility that the lung can be a target of graft-versus-host disease. They can happen late, something called IPS. It can happen early, acute, and it can happen late. And the classic lung problem related to transplant is called bronchiolitis obliterans, and we're going to talk a little bit about that today as well.

Here's the time course, and this is months after transplant. So early after transplant, you can have things called engraftment syndrome, diffuse alveolar hemorrhage. This is a very serious complication where sometimes our patients will cough up blood. And then there's this idiopathic pneumonia syndrome that we'll talk about in one slide. These are all considered early problems of the lung.

13:33  Lung problems that can occur late after transplant such as BOOP and BOS (bronchiolitis obliterans syndromes):  But late lung injury can also occur and, that can involve either something called BOOP, which is where your lungs get a little stiff or bronchiolitis obliterans syndrome where air can get in but can't get out. And I'm going to show you some cartoons that describe these two particular forms of lung injury.

So, here's some discussion points as we go through the next couple of slides. I want to talk about the clinical signs and symptoms of lung problems, compare and contrast the different forms of lung injury. What do we know? What drives these problems? What have we gleaned from mouse models? Which is something that my laboratory is interested in doing. Or what have we learned from the human disease process? And then we're going to finish up by talking about the approach to patients with lung problems, treatment strategies to consider, and future directions.

14:26  Illustration of bronchitis:  So, here's a couple of cartoons again. I alluded to this before, these are going to be the main kind of branches of the lung, the main branches of the tree. This is a normal bronchi. This bronchi has got some pus in it, this is not normal. There's some kind of inflammation. This is called bronchitis. Add itis to something and it's going to tell you that there's inflammation there.

14:49  What is pneumonia?  What about pneumonia? Remember, at the very tiny ends of the twigs, there are these areas where gas exchange, these air sacs are called alveoli. And if they get filled with pus, that is synonymous with pneumonia. Generally pneumonia is going to be from an infection, but bronchitis can be from infectious organisms or it can be from other exposures to the bronchial tree like smoking.

15:17  Bacteria, fungi and viruses that can cause infection in the lungs: So, we think about bacteria when we think of infectious problems. And, sometimes your docs will have you on medications like Levaquin or many others, Azithromycin perhaps.

Sometimes we worry about fungi, in which case you may be on Fluconazole or Voriconazole or Posaconazole.

We also worry about a germ called PCP. And your doctors may have you on Bactrim or Dapsone or Pentamidine to protect you from these particular types of germs.

There are also viruses that can cause inflammation in the lungs. And for that, many times your docs and nurses will be completing blood tests to kind of look to see if there's any evidence of viruses waking up in your body after the transplant process.

16:01  Idiopathic pneumonia syndrome (IPS) describes infections whose source cannot be traced:  So, what about non-infectious lung problems? Remember, about 50% of the time they're going to be infectious. The other 50%, no germs can be identified. When this occurs early in the time course of transplant, it's called idiopathic pneumonia syndrome or IPS.

And what this means is that our patients are actually getting quite sick. You can have cough and shortness of breath, you may need oxygen. In the worst case scenarios, there's a need for breathing machines. And this can actually come on very quickly after transplant.

This is an example of what a chest X-ray may look like. This is an X-ray of the chest, this big kind of a white blob here is actually the heart. You can see the ribs on each side, this is the shoulder. The lungs are here on either side of the trachea and the food tube. The lungs are filled with air, and they should be black. The fact that they're white is a bad thing. That means that there's inflammation in the lungs on both sides.

And this is an ominous, very serious side. And just a couple of years ago, this was an unacceptable outcome for patients with IPS. But some breakthroughs we've made in the lab have led us to come up with new therapies. When I first started in this field, this was an area that I was very interested in. I was particularly intrigued by how fast people got sick and how quickly from onset to just a week or two would go by and I would see these patients get sicker and sicker and have to go to the intensive care unit. This was back in the 90s when I was training. I was also impressed by how little was known about underlying disease mechanisms, and we had the opportunity to study the lung. Again, this is back in the early 90s, and so much progress has been made not just with the work that I've been blessed to do in my laboratory research efforts, but there are several other people throughout the country and throughout the world who are working hard on this problem.

17:57  Etanercept (Enbrel) is used to treat idiopathic pneumonia syndrome or IPS: And just as an example, we had come to find using those mouse models that this medicine Enbrel, which is a medicine that neutralizes the effects of a protein called tumor necrosis factor. Now, this medicine happened to be FDA approved for other problems like rheumatoid arthritis and psoriasis and things of that nature. So, when we stumbled upon this in the laboratory treating mice, we said, "This is great, this drug is already available." And it allowed us to bring a new kind of indication for this drug to our transplant patients to give them more hope to get through some of these life-threatening complications.

18:35  Bronchiolitis obliterans syndrome (BOS) affects 5-10% of patients after transplant:  So let's move to some of the more chronic forms of lung injury. So the one that is probably best known is called bronchiolitis obliterans syndrome. Now, this is a very kind of medical word on steroids here.

But remember what we learned, bronchioles, very tiny little branches in the bronchial tree of the lung. -Itis means that those bronchioles are inflamed. Obliterans means they're also clogged up. And you put that together with a syndrome, and this is what can plague many of our posttransplant patients.

It was initially described in their early 80s. You got a sense, the flavor for how a transplant has actually progressed since the 1960s. The incidence is probably in the 5 to 10% range thankfully. But this is still a problem when it actually is diagnosed.

So, there's evidence for airway obstruction. Remember those pulmonary function tests? Not so much a problem getting air in, but that forced expository volume at one second is down because you can't get air out. It's like having asthma but not being able to kind of fix it with an inhaler. Fixed asthma, if you will. Patients can have a dry cough, shortness of breath, wheezing. Many patients have no symptoms at all. X-ray findings can sometimes show changes, and sometimes they're completely within normal limits.

20:04 Question from audience residual air volume and BOS: With the air trapping, when you had mentioned the pulmonary function test and kind of the residual volume or something that was at the bottom, is that where that is?

Yes, yes. Great question. So what happens if you can get air in, but you can't get air out? What do you think happens to your residual volume? Does it go down or does it go up?

It goes up.

20:24  It goes up. It's exactly right. So, your residual volume, if you have air traffic, actually, is not going to be 100%. It's going to be 150% or 170% predicted because you can't get that air out. So that's exactly right. That makes me think that I taught you something today. You just made my day. But that's exactly right, you can get air in but can't get air out. And then your lungs get hyperinflated, and I can show you a quick picture I think of that here. But that's exactly the problem. People who have asthma can use an inhaler, and that relaxes the bronchial tree to get the air out.

21:02  Bronchiolitis obliterans syndrome is considered graft-versus-host disease of the lung:  But when you have bronchiolitis obliterans syndrome, it's not that easy, it's not that flexible. It's actually more fixed. So sometimes we need other medicines like steroids and things to help reduce some of that inflammation. But you're exactly right.

So, this occurs a little later, six months to years after transplant. Definitely associated with chronic graft-versus-host disease. In fact, it is considered chronic graft-versus-host disease of the lungs. If you happen to get peripheral blood stem cells, there is a higher risk of chronic graft-versus-host disease and bronchiolitis obliterans syndrome.

21:37  Treatments for bronchiolitis obliterans syndrome (BOS) or GVHD of the lungs:  Now, there's a bunch of treatments that you can use, steroids, Cyclosporine or Tacrolimus, some asthma meds, and Azithromycin, which is an antibiotic. We're going to talk about that. Problem is these medicines don't work too terrifically well.

21:50  How bronchiolitis obliterans syndrome (BOS) looks on a pulmonary function test:  So here's BOS, here are the pulmonary function tests. So remember what I said before, the closer you are to 100%, the better off you are.

But let's look at this real quick, FVC. That's a measure of how big a breath you can take. In this case, it's 80%, that's not too shabby, right? I mean, 80% is still within actually limits of normal. But here's that FEV one, it's only 43%. This means air is going in, but you can't get air out. And this is the classic PFT report card for bronchiolitis obliterans syndrome.

If we take a biopsy of the lung and look at it under the microscope, this is supposed to be one of those little airways. All of this is scar, this is collagen, this is collagen deposition. This is all scarred, and you can get the sense that that airway is obliterated, hence the term bronchiolitis obliterans. And here's how it again looks in the cartoon, very end of the small twigs, you get a blockage in there, inflammation around those airways.

Air can get in. It's almost like a ball valve trap, air can get in, but then it can't get back out. The lungs get hyper-inflated.

23:04  Pulmonary problems often don’t have symptoms early in the course of the disease:   So, what do we know about this? This was actually a publication just a couple of years ago by Dr. Palmer and colleagues. And they looked at decline in lung function, and they found that declines in lung function predate symptoms, which means you can have changes in your lungs and not even know it. And the only way we can figure this out is by doing these pulmonary function tests. Because if you wait until you have shortness of breath or a cough, well that actually predicted outcome. And the outcome here was not a good one. So it makes sense if you're waiting until you are symptomatic from what is going on in your lungs, you're probably further down the slope going in the wrong direction.

If you had increasing scores over time, could correlate it with outcomes. So if your scores went up, if your symptoms went up, that ended up not being good for the patients. And here's an example of that. You could actually find change in pulmonary function long before people started developing wheezing or cough, et cetera. And I actually had the good pleasure of writing an editorial on this called window of opportunity. This is where we want to capture our patients. We want to know before you start coughing or wheezing that lung function may be going down. If we're going to have a better chance at treating this and making it better, you want to capture something early.

24:24  Bronchiolitis obliterans syndrome with organization pneumonia (BOOP) is a rare complication after transplant:  So, this is another form of lung injury that's actually pretty rare as well, but instead of being called BO, this is called BOOP. And many times people interchange these two terms, but they're actually very different.

This is also inflammation in the lung, it's relatively uncommon, thankfully, single digits. You can also have a dry cough, shortness of breath, need oxygen. The X-ray changes? are different. And in this case, the pulmonary function test report card is more restrictive. It's not so much you can't get air out, you have difficulty getting air in. The lungs are actually stiff.

It can occur after transplant, months to years after. Risk factors do include chronic and acute graft-versus-host disease. This is a little bit more responsive to steroids in general. But sometimes after transplant is still challenging. The terms, as I mentioned, BOOP and BO can be used interchangeably or they are, but they're really not the same thing. So, it's important for people to know that.

25:28  Pulmonary function test for someone with BOOP:  So here is a pulmonary function report card for someone who has BOOP. In this case, FVC is 70%, so this is down. The lungs are stiff, you cannot get air in.

You can get air out pretty well, it's never going to be 100% if your air going in is low, but this ratio is close to 100%. So, this is different, this is more almost like pneumonia where the lungs are actually stiff rather than having problems getting air out.

And here's the picture, the cartoon of BOOP where you have inflammation not only at the very small twigs of the airway, but also getting into these alveolar structures. So, it's more as the term implies like organizing pneumonia, and that makes your lungs stiff. Here's a CAT scan finding a BOOP. You have, what are called, these big fluffy infiltrates on either side.

26:22  What causes lung problems after transplant?  So, what are some potential causes of lung problems after a transplant? Well, we do know that sometimes the effects of conditioning regimen, chemotherapy, and radiation can affect the lung.

Sometimes you can have a hidden infection or we just came to learn some very startling news at one of these conferences, maybe a prior infection. So sometimes you get a cold, you get a respiratory tract infection. It comes and goes. Then three or four months later, you're short of breath. Doctors check you out, can't find any germs. But we find problems in the lung. We say, "This is non-infectious, we can't find any germs." Well, maybe it was a hit and run. Maybe we're seeing the end results of an infection that our patient had three or four months ago. So, we have to keep that in mind.

Is it the immune system gone wild? Is this graft-versus-host disease where you have inflammatory proteins and some of the immune cells from the donor graft, the ground troops, as I like to call them, that cause graft-versus-host disease now attacking the lung? Is the lung a target of graft-versus-host disease? It certainly is in the chronic setting.

27:35  GVHD of the lungs develops slowly over time:  How do we know about what is driving these processes? Here's our fine furry friends, the mice that we use in our laboratory to study bone marrow transplant. So we actually do bone marrow transplants in mice, and they can be transplanted either with identical twins or a mouse strain that is mismatched. So, we can pretty much replicate just about any type of transplant in the mouse.

And guess what, animals that get syngenetic or identical twin transplants, their lungs look beautiful. But the animals that get graft-versus-host disease, their lungs get very inflamed. All of these purple cells are immune cells from the donor that are causing inflammation in the lungs. And we can begin to learn about that. And if we watch the animals over time, guess what happens, these lungs look very chronic much like we saw under the microscope with a human who has bronchiolitis obliterans. So, we can actually mimic some of the same problems we see in patients in our mouse models.

And with that, we've come to believe that perhaps what goes on in the lungs doesn't happen overnight. Maybe this is a slow progression, maybe there's some early inflammation that's maybe causing a little bit of cough or no symptoms at all. But if the body is not repairing and healing that, what can happen over time is you can begin to get more chronic inflammation specifically around those small airways or maybe throughout the lungs. And if that goes unchecked and you develop fibrosis or scarring in the lungs, that's where the lungs can either have this problem of bronchiolitis obliterans where air gets in but it doesn't get out or where your lungs get stiff where you just have difficulty getting air in. So we're using mice to kind of learn more about what drives these processes so we can learn how to prevent these problems and treat them.

29:29  B-cells may be responsible for GVHD in the lungs:  And it turns out, I talked a little bit about the ground troops, and this is just one kind of a cartoon from a paper we just published that B cells, which here before have not been really a big driver of graft-versus-host disease may actually be very important in driving lung problems. And, these B cells can get activated in certain parts of the body called germinal centers. They can cause activation of other cells in the body and then lead to the deposition of collagen. And that leads to the development of scar and fibrosis.

So I show this only to kind of give encouragement that we are looking hard to try to figure out what is driving this process. And now this is leading to new interventions that we'll talk about. So we're going to finish up with a couple of slides that talk more about tests and procedures and consultants, things that you guys should be aware of or be going through if you have lung problems.

30:27  How do doctors determine if you have GVHD in the lungs?  So, it all starts with history and physical exam. I don't care how good CAT scans are or how good we can do pulmonary function tests, your physicians, your practitioners have to sit down with you, get a good history, and you have to be good historians. You have to tell us what is going on, what is bothering you.

We're going to do all sorts of assessments, we can do oxygen levels. We put that little clip on your finger and get what's called pulse oximetry. We may want to do pulmonary function tests. We've talked about X-rays and CAT scans that are going to be important. There may be consultations with specialists in pulmonary medicine, and you may need to undergo a couple of procedures. One called bronchoscopy, where a tube will go down into your windpipe, fluid will be flushed into the lungs. That fluid can be taken out and then sent for tests.

And then rarely we do need to consult with surgeons, and sometimes get lung biopsies or tissues of the lungs. So we want to be able to identify patients at higher risk for problems in their lungs. And then you guys need meticulous and regular histories and physicals. If there's early recognition of respiratory problems, we're going to skip down, I'll show you in a second, to number six.

31:35  Regular pulmonary function tests are important to detect and manage GVHD in the lungs: But this is something I'm a big stickler of. I don't think we do enough pulmonary function tests. I think you need to do these particularly in a high risk patient. Who's a high risk patient? Matched unrelated donor, mismatched donor, easily high risk. For me, all of my patients are undergoing PFTs three to four times a year for the first two years because I want to see the change in lung function before my patients have cough or shortness of breath because I think that is a time to intervene.

32:06  What happens if you have abnormal pulmonary function tests?  If the PFTs are showing an abnormality, I don't know that we have to necessarily throw up a three alarm or five alarm fire, but now I'm going to follow them even more closely and see, are they really sliding down? Is there restrictive lung disease? Are the lungs stiff, or is there obstructive lung disease?

And if lung decline continues, that's where we want to do further evaluation. Is there an infection present? If yes, we want to treat. If no, we might want to see if there's evidence for graft- versus-host disease in other organs and then consider steroids or other medicines that are now becoming available. This is the other thing I would really encourage everyone in the room, not only to ask your docs to follow PFTs more closely but also see if a clinical trial is available if it looks like you're having lung problems.

32:55  Medicines available to treat GVHD in the lungs:  I mentioned this medication, Enbrel that we use in patients who've had sub-acute or chronic lung problems. There's a new drug, FDA approved first one for chronic GVHD called Ibrutinib. This medicine is still now being tested in kids and in larger populations of adult patients. There's a combination called FAM, which includes an inhaled steroid, an antibiotic, and a medicine that decreases immune cells from getting into the lungs. Generally pretty well tolerated, that medicine or combination has been used for lung problems. Some people will use ECP, you may have heard this, Extracorporeal Photochemotherapy. It's a way to take blood cells out of the body, treat them outside the body and put them back. Suffice to say, there are options available if you have lung problems.

33:44   How to protect your lungs after transplant:  So, what about good take home messages for all of you guys as we finish up?

• Firstly, of course, do your best to take care of yourself. Don't smoke for sure, and, stay away from people who are smoking. This really, again, really refers not only to our patients, but their caregivers.
• Stay away from crowds and individuals who are ill.
• Ask your doctors and nurses about pulmonary function tests, particularly if you're still feeling good because you want to find out if there's problems with pulmonary functions before you become symptomatic.
• Let your team know as soon as you're having any kind of breathing problems, don't try to tough it out. If you start noticing as you're climbing up stairs, you're a little short of breath and that persists for a couple of days, let your nurse practitioners or physician assistants or doctors know. That can be an early sign that something is going on.
• Take your prescribed medicines even when you're feeling good, your antibiotics. These things are to protect you from getting an infection, which if you have a lung problem can make it that much more challenging for you guys.

34:47   New therapies being developed to treat lung problems after transplant:  So, what about the future? Clinical studies, medicines like etanercept that neutralize tumor necrosis factor.  I mentioned this combination of medicine called FAM.  Ibrutinib for chronic graft-versus-host disease, the first FDA approved drug in this space ever.

 I've mentioned to you that my colleagues and I have been meeting, this actually goes back to 2014. We know that this is a problem, we are looking to update on the diagnosis and treatment of lung injury, updates on the biology of chronic lung injury, what is driving this? This will hopefully help us come up with new ways to prevent and treat this problem.

35:27  Summary of talk:  So, in summary, lung problems are a significant issue after transplant. They can occur early and late. In each scenario, lung problems do have a big impact on outcomes. And we want our patients to be alive and thriving, there is no question.

35:44  The cause of lung problems is complex and being studied:  The cause of lung problems is complex, but we're using animal models to try to figure this out, to try to see if there's a connection between acute and chronic inflammation in the lung.

The important role for B cells, maybe this protein tumor necrosis factor is a common thread between early and late lung injury. We know more needs to be done clinically, and we are working hard to help standardize the way we look at and work up lung disease.

 I think more frequent surveillance of pulmonary function will be helpful. We're trying to come up with new clinical trials to make new promising medicines available to our patients. So I will end with some acknowledgements to my colleagues at Johns Hopkins, the people in my laboratory, of course, to our patients and their families. Funding support that I've been blessed to have over the time, including a shout out to the Meredith A. Cowden Foundation, and Jerry Cowden is here today. We have been friends and colleagues for a long time since my time back in Cleveland.

So I will end with this. Some secrets to success, remain passionate and committed, embrace teamwork and comradery, find a good mentor and then be one, that can be in medicine, that can be in business, that can be in life. My favorite, be too good to be ignored. I found this in a fortune cookie one time. Find your happy place, very important. And we are committed in the academic medical community to raise the standard of care so that outstanding clinical research really is synonymous with best clinical care. And I'll end with one of my recently found happy places, this is not too far away. This is actually Lake Tahoe. These are my two boys, Christian and Liam, and I will leave you with this, some spiritual food for thought.

So, thank you for your attention. We have a good amount of time, maybe 20 minutes or so for questions. So thank you for your attention.

Question and Answer Session:

Am I correct in understanding that the onset of lung problems related to graft versus host onset is about two years for that?

37:55  When do lung problems occur after transplant?  So, the question again is, when is the onset? The onset really can start anywhere from about six months through that two-year range. It can't even be longer, but it's a comparison to things that happen within the first couple of months, and things that can happen months to years out. So I think that is a very reasonable range to be thinking about these more chronic forms of lung problems.

38:21  How do you tell the difference between fatigue due to deconditioning after transplant and fatigue due to lung problems?  Having gone through transplant, there's tons of fatigue and you kind of have this potential deconditioning, how do you kind of ferret that out from the very initial stage of maybe this lung injury kind of in that early stage?

38:37  Yeah, these are great questions. And this is where I think close observation is important because we do get deconditioned. Anytime we're sick in the hospital for any length of time, you will be deconditioned. And that results in not being able to walk as far, not being able to run if you're a runner, and being short of breath.

So, the interesting thing or the important thing is to follow those symptoms over time. Check and see. Pulmonary function can still be pretty normal even though you're fatigued, that's a different reason to be short of breath. But if you get stronger and stronger as you get out of the hospital, if your pulmonary function tests look good, that report card is still in a reasonable range, then I think you know that this might be just reversible deconditioning.

On the flip side, if you had been feeling good and you're out of the hospital and now it's maybe a year out. And boy, I'm thinking, "I got some of this behind me, my leukemia, my lymphoma is in my rear view mirror. Why the heck am I having trouble walking upstairs? Something is wrong here." Now is the time to think, there may be something else that's going on.

And this is where I don't think people's lung function falls off a cliff. So what happens is sometimes you get PFTs that are 100, and then nothing again until a year or two years out. And then suddenly there's a shortness of breath that comes up. And when your lung function is finally tested, it stinks. You're failing on your report card. I don't think that happened overnight, it almost certainly hasn't.

40:06  Handheld devices are available to measure pulmonary function:  So, this is where you want to check and see like that one study showed, you can see changes in lung function before you see changes in symptoms. And the only way to pick that up is if you're doing pulmonary function tests. And people I will say are now coming up with handheld devices where you don't have to go in and get into that chamber and put a clip on your nose. You can actually follow a couple of important parameters with a handheld device just to get some general readings. And if those quick readings are sliding down, then you can go to your doc and say, "Hey, here's recording. I think you need a full pulmonary function test to see what's going on." This is where I think where we need to be to kind of nip these things in the bud before they become a problem.

Very helpful, thank you.

They're now commercially available, I don't use a lot of them. But as I just mentioned, I was with a bunch of my colleagues in the NIH and the one lung function doctor from the Seattle, Fred Hutchinson had one of them with her. So she's now following her patients with these little devices. We can google it, we can ask Dr. Google. We can find these things, they are available. But this is something I'm very interested in using myself.

Now, I'm a pediatrician so you have the issue with children being able to do it, but they are now available. So I would talk to your physicians about that to see if it's something you can use to at least monitor even if they're trends. Even if you know you're scoring 70 for you, and then suddenly it's 65 and 60. That trend may be able to be enough to say, "Hey, maybe we need another check," or, "maybe something is going on before we're getting cough and shortness of breath."

These are simple things that we can do. We had a lot of discussion, after all of the science and how we're going to figure this out in the mouse, we need to follow pulmonary function more carefully over the course of time and standardize the way we're going to approach this in our patients. These are, I call them boring but important. It's not really cool, sexy science, but it's important for us to understand what the history of diseases and to try to intervene before symptoms actually develop.

42:19  Can chemotherapy and radiation cause lung problems? Can chemo and radiation cause something kind of like IPF, like scarring of the lungs where you cannot actually transfer oxygen into the blood?

 You bet.

42:32  How do lung problems before transplant affect lung health after transplant? Because that seems to be more my issue because it seems like a lot of my lung problems actually predate transplant. And then transplant just kind of worsened everything.

[Dr. Cooke] Yes. So these are great points. Sometimes we're lucky enough to have our patients come into transplant. We all do lung function tests before, we love to see the report card look great before transplant, but sometimes it's not. And if it's not, you may have gotten a reduced intensity preparative regimen because of that, because your lungs may not have been healthy enough to get a lot of chemotherapy or radiation. And this is probably what you're unfortunately dealing with right now.

This is a picture, it's not meant to be a small airway. These are the, they're called fish net kind of architecture in the lung. This is where the gas is exchanged again. But when this gets stiff or when this scars, this is what ends up happening. The lungs get stiff, you can't get air in. Now, sometimes that happens long before transplant, again from other chemotherapies that you may have undergone before getting to transplant.

43:32  Steroids don’t help with scarring in the lungs:  But this, we would prefer to catch people either here, maybe the lung function tests are starting to slide down. They're not bad, but they're not the same as where you started. Maybe even here because there's still inflammation. This is where steroids and all of these medicines that suppress the immune system, this is where they're going to work. If you get to this point, it's more difficult.

Steroids are not going to help here because this is now scarred. The lungs don't like scarring. It's not like a scar if we cut our hand or arm, you can get a scar. You get a lot of scar in the lungs, it's difficult to break this down. Not impossible, but more difficult. And this is where we need to pay very close attention to avoiding things like smoking or second-hand smoke, to try to do everything you can to stay away from getting infected. Because if your lungs are already only working at 50%, an infection can really make you feel that much more terrible.

So, this is a tough place to be. It's important that we remain very supportive, trying to do as much as you can, people will call it pulmonary rehab. You can talk to your physicians about that. Sometimes there's some therapies that can be done to help keep your lungs nice and clean and perhaps build up your endurance otherwise. But this is what we really want to try to avoid. And if we're going to capture patients to treat them successfully, we actually want to capture them at a time where there is some active inflammation because this is where steroids and other medicines that suppress the immune system actually work.

45:08  Hi, Dr. Cooke, good to see you again. Can scleroderma impact the lungs?

45:15  How scleroderma impacts breathing: This is a great question as well. I'll just weave this back up again. I was speaking specifically about the lungs themselves and how elastic they can be, but we have to remember that your lungs are surrounded by your chest wall.

So sometimes patients who have skin GVHD and scleroderma, tightness of the skin, that can also impact lung function because you just simply cannot move your chest enough to get air in and out. This is a very dynamic process. There is a muscle called the diaphragm that has to work to move, and we have respiratory muscles in our chest that also play a big role in breathing. So if the chest wall is sclerosed or really thickened, that can also affect lung function as well. It's usually the restrictive kind not so much the obstructive kind, but absolutely. So sometimes you can have almost like a double whammy there, inflammation or scarring in the lungs and even around the lungs.

46:18  And follow-up, can photopheresis help with lung issues.

46:25  Can extracorporeal photopheresis (ECP) help with lung problems?  It's one of the things that I put up there. And the answer to that is, yes, you can find evidence in the literature, in the published literature that this photopheresis or extracorporeal photopheresis or extracorporeal photochemotherapy ... Does anyone ever had that in the room? People know what that is?

So, this is where you would have sometimes fairly large catheters or you can either have them inserted or you can use a central catheter. Blood gets taken out of the body basically through a center fusion. It's treated outside of the body and then put back in. It's a little bit of a magic box, we still don't know for sure what is going on there. But it definitely helps with skin graft-versus-host disease. So if you have that scleroderma, this can help kind of loosen up the chest.

There are reports that it can help bronchiolitis obliterans syndrome, but it's a little patchy. Unfortunately, a clinical trial that was set up to test that specifically didn't end up being completed, which was really disappointing from our perspective. But, yes, that is an option to at least entertain. It's a little cumbersome as you know, it's not taking a medicine. You got to go a couple of times a week, sometimes once a week, then every other week. But if you have good results from it ... Did you think you got good results from ECP?

47:39  [Audience member] Dr. LeMaistre said that he really doesn’t know whether it's coincidence to the treatment that there's a decline in the scleroderma. There's no proof to it. But yes, it seems to be improving scleroderma. Scleroderma, also being a disease of skin and connective tissues., it's all the tissues in the body which had throat, couldn't swallow, gut issues, all this sort of thing, that was all part of the scleroderma. I thought maybe the lungs could have been impacted too. It seems that when I started Sirolimus or ...

48:17  Rapamune.

48:17  Rapamune, and the photophoresis that all of that, I had lung issues as well, but it seemed to all decline about same time in the same rate.

Well, I'm glad you had some response to it, and it is interesting. I mean Dr. LeMaistre has been around for a long time. But listen, if it works, who cares how it worked. And if it were maybe by chance, as long as people are getting better. But those are the things that we're trying to learn more about. The more we learn about what drives a certain problem, the more we can understand better what may again be used to treat or prevent it. If we have a little bit more... do we still have a couple of minutes?

A couple of minutes, yeah.

48:56  How parametric response mapping can help track lung problems:  I want to show you something else, this is kind of cool stuff. No one bid on my Iraq war thing, so I will pass on this. But this is one of my paradigms. This I want to tell you guys about.

So, this is kind of new stuff that's a little scientific but it's kind of cool. It's called parametric response mapping. Now, let me give you the skinny on this. This is considered an imaging biomarker, high sensitivity and it's feasible. So this is a special test. How many people in the room have had a CAT scan, high-resolution CAT scan? Almost everyone. There's nothing more to do except a high-resolution CAT scan where you take inspiratory views, take as deep breaths as you can, hold it. They do a picture, and expiratory. If you have a high-resolution CAT scan, inspiratory and expiratory, you can use that scan and get this extra information.

It's basically a computer program. It takes this high-resolution CT scan, inspiratory and expiratory views. And then it kind of breaks the lung down spatially into what is called voxels. So they have little boxes that make up the whole lung, on inspiration and then on expiration. And the computer system can actually make them kind of move from inspiration to expiration, and then they put them together. And in doing this, they come up with a color code that looks at changes that can distinguish normal lung, you'll see in green, small airways disease, the bronchioles. I want you guys to remember the tree and the twigs. That's the bronchioles. Emphysematous changes, which are a little different, and even fibrosis or scarring.

So, what does this do? This is a CAT scan. Now, it's a little hard to see because we're looking at yellow and green. But you have to trust me, for the most part, this is green. There's some yellow in here, but this is one month after transplant, the high-resolution CAT scan is completely normal. Patients got a little bit of symptoms, and we're seeing mostly green but some yellow. Two years after transplant now, the high-resolution CT does not show any air trapping. There's really not so much going on except on pulmonary function tests, the patient is now meeting criteria for this BOS problem, but this is now a year later. And the point here is, I don't know if you can tell, this is more yellow now than green. This was more green than yellow.

But the take home point is even a year before with a negative high-resolution chest CT scan and pretty normal PFTs, this was starting to pick up some problems. And then look at this, this is now years later. This is not one of my patients, thankfully, because this is now five years and the lungs are actually getting worse and worse. Now, you can see these lungs are not only yellow, but you see the smattering of a darker color here, that red. This patient actually needed to go on and actually get a lung transplant believe it or not for their bronchiolitis obliterans. But the point here is it's more sensitive, you can pick up subtleties in what's going on in the lungs even before a plain old CAT scan. And then after a successful lung transplant, you see that the lungs are more green again.

The point of this is that you can actually begin to pick up without ... This is noninvasive, it basically is made off of a standard CAT scan. So, my colleague Yanik who I worked with for years at the University of Michigan and his colleagues are really kind of championing this in the transplant setting. So this would be another thing to talk to your colleagues about, parametric response mapping. And it basically is just a fancy way to look at a high-resolution CAT scan of the lungs. But hopefully it'll start giving us some ideas of if what's going on in the lungs is from small airways disease and bronchiolitis obliterans or is it from infection or what have you? But this is the kind of stuff we're really trying to move forward so that we can have more sensitive indicators of what is going on in the lungs before our patients have problems with cough or shortness of breath.

Well, I think that's a good question. When will we do something like this? I would think you would do it, you got to be following along. If we're not paying attention, then these innovations don't help. But if you're starting to do some pulmonary function tests and you're starting to see some declines and you get that high-resolution CT scan, that is then something you can check and see, "Hey, are we detecting something early here?" And if it looks good, you continue to follow the PFTs. Maybe the pulmonary function tests settle out a little bit, and we step back. But you cannot gain any of the advantages if we're not looking. And when I say we, I mean we, the physicians and the practitioners have to be ordering the tests. And, of course, you have to be well enough and willing to actually do the pulmonary function test. But this is important stuff because I think we're going to be most successful as we are in almost every case if we intervene early.

Okay. Thank you. Dr. Cooke for a great presentation.

Pleasure is always fine, enjoy the rest of the afternoon.

All the great questions too.